title: JAK1/2 and Pan-deacetylase inhibitor combination therapy yields improved efficacy in preclinical mouse models of JAK2V617F-driven disease.
abstract: OBJECTIVE
  The myeloproliferative neoplasm myelofibrosis is characterized by frequent deregulation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling, and JAK inhibitors were shown to reduce splenomegaly and ameliorate disease-related symptoms. However, the mutant clone and bone marrow fibrosis persist in the majority of patients. Using preclinical models, we explored whether JAK and pan-deacetylase inhibitor combination yielded additional benefits.
  
  
  METHODS
  The combination of the JAK1/2 inhibitor ruxolitinib and panobinostat was investigated using two different mouse models of JAK2(V617F)-driven disease. A Ba/F3 JAK2(V617F) cell-driven leukemic disease model was used to identify tolerated and efficacious doses. The drugs were then evaluated alone and in combination in a mouse model of myeloproliferative neoplasm-like disease based on transplantation of bone marrow transduced with a retrovirus expressing JAK2(V617F). Exposures were determined in blood and tissues, and phosphorylated STAT5 and acetylated histone H3 pharmacodynamic readouts were assessed in spleen and bone marrow. Histologic analysis was conducted on spleen and bone marrow, including staining of reticulin fibers in the latter organ.
  
  
  RESULTS
  The combination of ruxolitinib and panobinostat was found to have a more profound effect on splenomegaly, as well as on bone marrow and spleen histology, compared with either agent alone, and the analysis of pharmacodynamic readouts showed that ruxolitinib and panobinostat have nonoverlapping and complementary effects.
  
  
  CONCLUSIONS
  Combining JAK1/2 and pan-deacetylase inhibitors was fairly well tolerated and resulted in improved efficacy in mouse models of JAK2(V617F)-driven disease compared with the single agents. Thus, the combination of ruxolitinib and panobinostat may represent a promising novel therapeutic modality for myeloproliferative neoplasms.
authors.affiliation: Authors' Affiliations: Disease Area Oncology and Preclinical Safety, Discovery and Investigative Pathology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Emeline
authors.initials: E
authors.lastname: Evrot
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ebel
authors.forename: Vincent
authors.initials: V
authors.lastname: Romanet
authors.forename: Claudia
authors.initials: C
authors.lastname: Roelli
authors.forename: Rita
authors.initials: R
authors.lastname: Andraos
authors.forename: Zhiyan
authors.initials: Z
authors.lastname: Qian
authors.forename: Arno
authors.initials: A
authors.lastname: Dölemeyer
authors.forename: Ernesta
authors.initials: E
authors.lastname: Dammassa
authors.forename: Dario
authors.initials: D
authors.lastname: Sterker
authors.forename: Robert
authors.initials: R
authors.lastname: Cozens
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
authors.forename: Masato
authors.initials: M
authors.lastname: Murakami
authors.forename: Fabienne
authors.initials: F
authors.lastname: Baffert
authors.forename: Thomas
authors.initials: T
authors.lastname: Radimerski
mesh_terms: D000107:Acetylation; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009570:Nitriles; D000077767:Panobinostat; D011087:Polycythemia Vera / Q000188:drug therapy; D055728:Primary Myelofibrosis / Q000188:drug therapy*; D011720:Pyrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines; D012155:Reticulin / Q000032:analysis; D050799:STAT5 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013163:Splenomegaly / Q000188:drug therapy; D013922:Thrombocytosis / Q000188:drug therapy
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D012155:Reticulin; D050799:STAT5 Transcription Factor; C540383:ruxolitinib; D000077767:Panobinostat; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D006655:Histone Deacetylases